Plasmodium Falciparum Virulence Determinants Unveiled Comment Brendan S Crabb and Alan Cowman
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central http://genomebiology.com/2002/3/11/reviews/1031.1 Minireview Plasmodium falciparum virulence determinants unveiled comment Brendan S Crabb and Alan Cowman Address: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia. Correspondence: Brendan Crabb or Alan Cowman. E-mail: [email protected] or [email protected] Published: 25 October 2002 reviews Genome Biology 2002, 3(11):reviews1031.1–1031.4 The electronic version of this article is the complete one and can be found online at http://genomebiology.com/2002/3/11/reviews/1031 © BioMed Central Ltd (Print ISSN 1465-6906; Online ISSN 1465-6914) Abstract reports The human malaria parasite Plasmodium falciparum, one of the world’s most devastating pathogens, has an astonishing array of sequences and genes that play key roles in pathogenesis and immune evasion. We must understand the functions of these elements if the chronicity and unpredictable virulence of Plasmodium is to be explained. deposited research Despite intensive efforts over the last century to understand deep microvasculature of various tissues and organs, and is and control malaria, the causative agent of the most severe associated with certain severe disease outcomes (reviewed in form of the disease - Plasmodium falciparum - remains firmly [8-10]). A parasite protein inserted into the infected red blood entrenched as a leading cause of morbidity and mortality in cell surface, known as P. falciparum erythrocyte membrane humans. Approximately 300-500 million clinical episodes and protein 1 (PfEMP1), is considered to be a key adhesive ligand 2.7 million deaths are attributed to P. falciparum infections mediating sequestration. In a process known as antigenic vari- each year and, with the emergence of widespread drug- ation, clonal P. falciparum parasites can vary the type of refereed research resistant parasite populations and insecticide-resistant mos- PfEMP1 molecule they express, so as to avoid antibody-medi- quitoes, this situation is predicted to worsen [1]. New ated clearance. Intriguingly, different PfEMP1 ligands mediate cost-effective strategies for controlling malaria, such as the adherence to different receptors on endothelial cells, including development of a vaccine, are urgently required. The complete the scavenger receptor CD36, chondroitin sulfate A and intra- sequence of the 14 linear chromosomes that comprise the cellular adhesion molecule-1. In some instances, parasite pop- P. falciparum genome has recently been determined [2-5]. It ulations with a predisposition to adhere to certain receptors is perhaps not surprising for such a successful pathogen that are more commonly associated with certain disease outcomes, these studies have revealed that a high proportion of the 5,300 such as cerebral and placental malaria, although the precise predicted genes encode proteins known or predicted to play a role of parasite-receptor interactions in determining disease interactions role in pathogenic processes, such as invasion of red blood severity remains to be understood. P. falciparum infections cells, cytoadherence and immune evasion. We have reviewed are persistent, and this chronicity is promoted by antigenic elsewhere the impact of the genome sequence on red blood variation at the infected red blood cell surface. Proteins of the cell invasion [6]; in this article, we comment on our increased repetitive interspersed family (rifins) are also expressed at the understanding of the virulence genes that encode proteins surface of infected red blood cells, and, like PfEMP1, these involved in cytoadherence and immune evasion. Insight into undergo antigenic variation [11,12]. Another family of proteins the function, diversity and regulation of these genes promises related to the rifins has also been described - the subtelomeric information to reveal new strategies for fighting malarial disease [7]. variable open reading frame (stevor) proteins - but their func- tion remains unknown [11]. PfEMP1 and rifin proteins are considered key virulence factors in P. falciparum. Cytoadherence and antigenic variation The adhesion of parasite-infected red blood cells to vascular The PfEMP1, rifin and stevor proteins are encoded by endothelium leads to sequestration of P. falciparum in the members of the var, rif and stevor gene families, respectively 2 Genome Biology Vol 3 No 11 Crabb and Cowman [11,13,14]. As a measure of the significance of these genes directly adjacent to the non-coding subtelomeric repeats to parasite survival, it is now evident that around 10% of ( igure 1); but 23 of the 59 var genes are found in central the 2.3 megabase P. falciparum genome is committed to locations on chromosomes 4, 6, 7, 8 and 12, mostly in the expression and generation of diversity of these viru- head-to-tail arrays of between three and seven genes (see lence genes. This includes the genes themselves - a total of igure 1, top). 59 var, 149 rif and 28 stevor genes - as well as intergenic (regulatory) regions and non-coding subtelomeric repeat regions thought to contribute to diversity and transcrip- The subtelomeric region tional control of the neighboring virulence genes (these are rom the genome sequence, it is clear that most of the 28 discussed in more detail below). Members of the var, rif P. falciparum chromosome ends are structurally highly and stevor gene families are mostly concentrated at the conserved, and each end can be divided into five different end of each P. falciparum chromosome and are positioned subtelomeric blocks comprising up to 120 kilobases each SBs CCB SBs Central var array 60-120 kb (Chromosomes 4, 6, 7, 8 and 12) var rif(n) stev rif(n) stev B Rep20 var rifvar rif(n) stev rif(n) B A Rep20 var rifvar rif(n) stev rif(n) Telomeric cluster Telomeric B A at nuclear periphery at nuclear Rep20 SB1 SB2 SB3 SB4 SB5 (tel) (TAREs 1-5) (TARE6) (var + repeats) (Virulence genes) Figure 1 Conserved structures at the ends of P. falciparum chromosomes. A typical chromosome is shown at the top, highlighting the position of subtelomeric blocks (SBs) and centrally located var gene arrays that occur on only a subset of chromosomes. Three typical chromosome end structures are expanded in the lower section and are represented as clustered at the nuclear periphery [19,20]. For all chromosomes, SBs 1-3 are highly conserved in both order and sequence - the individual boxes represent telomere-associated repeat elements (TAREs) 1-6, as previously described [16] - while cross-linking mediated by SB3 (made up of the degenerate 21 base-pair repeat known as Rep20; shown in blue) has been implicated in the stabilization/formation of chromosomal clusters within the cell nucleus (gray ovals) [18]. The first transcribed var gene is typically transcribed toward the centromere in SB4 (for 22 of the 24 chromosomal ends that have a terminal var). The predominant ‘type 1’ var genes (colored red) are found in the positions shown. A, B and C represent var upstream sequences, upsA, upsB and upsC, respectively, that are typically found upstream of var genes in the locations shown (note that upsB is found upstream of both subtelomeric and internal var genes). The rif, stevor and var genes in SB5 have a common arrangement in some, but not all, chromosome ends. For example, the arrangement of telomere-var-rif/stevor(n) shown at the top of the cluster in the figure is found at 10 chromosome ends, but even among this group there is variation in the arrangement and orientation of transcription of the rif and stevor genes. Hence, although chromosomal clustering within the nucleus promotes ectopic recombination and the generation of diversity in virulence genes [15,19], this is likely to be limited by the variation in the gene structure within SB5. http://genomebiology.com/2002/3/11/reviews/1031.3 ( igure 1) [2]. Three subtelomeric blocks (SB1-SB3) are cysteine-rich domains). Although 16 different var types non-coding, while the remaining two (SB4 and SB5) incor- were identified in the sequenced 3D7 genome, 38 of the 59 porate virulence-gene family members amongst other var genes in this parasite line were of the same four- comment sequences ( igure 1). SB1 is located at the extreme terminus domain type, termed type 1 [2]. It is striking that the 38 and is comprised of approximately 1.2 kb of a seven base- type 1 var genes are not distributed randomly but are pair G-rich telomere repeat with the consensus sequence found either at the extreme telomere, where they are GGGTT(T/C)A [15]. SB2 and SB3 together are 30-40 kb in always present in a telomere-to-centromere orientation, or length and comprise six different non-coding repeat ele- in central chromosomal locations, where they comprise 20 ments previously known as telomere-associated repeat of the 23 var genes in this region. The dominance of one elements (TAREs) 1-6 [15,16]. var type was unexpected, as previously characterized var genes to which an adhesive phenotype had been assigned reviews Although subtelomeric repeats have been identified in other were generally not of this type, and indeed encoded more organisms, the P. falciparum SB2 and SB3 elements are than four domains. unique in eukaryotes, and even amongst the Plasmodia, in terms of their size, composition and complexity. SB2 com- The mechanisms that control expression of the P. falciparum prises a series of five ordered repeat elements (TAREs 1-5) virulence genes remain poorly understood. In the case of that are interspersed with non-repetitive sequence. These var genes, at any one time all but one are repressed. A elements are always found in the same order, and they cooperative interaction - which does not depend on chro- display remarkable sequence conservation and a CG-bias mosomal context - between the var promoter and intron reports (around 30% G+C) that is unusual in the non-coding regions can mediate this silencing [21], but the mecha- regions of the otherwise extremely AT-rich genome (nor- nism(s) that control var gene activation and switching mally about 10% G+C in non-coding regions and 19.4% G+C remain to be determined.